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The 25(OH)D 3 /1,25 (OH) 2 D 3 24-hydroxylase (24-hydroxylase) displays an induction profile responsive to vitamin D (D) abundance and is hence only observed in normal extracellular Ca 2+ concentrations. However, the participation of Ca 2+ in the expression of the 24-hydroxylase gene in vivo is not known. The present studies investigate the role played by the circulating Ca 2+ and the D 3 and/or 1,25(OH) 2 D 3 status on the 1,25(OH) 2 D 3 -mediated inducibility of the 24-hydroxylase gene in rat duodenum. Hypocalcemic D-depleted rats were supplemented with calcium alone to normalize serum Ca 2+ without normalizing the D 3 status or were acutely or chronically supplemented with D 3 or 1,25(OH) 2 D 3 . Messenger RNA for the 24-hydroxylase was undetectable in the intestine of hypocalcemic D-depleted rats, and short- or long-term calcium supplementation was completely unsuccessful in inducing its expression. By contrast, acute 1,25(OH) 2 D 3 administration led to significant increases in the levels of expression of the gene which was independent of the calcium intake, the prevailing circulating Ca 2+ , and the D 3 or 1,25(OH) 2 D 3 status. Moreover, 24-hydroxylase gene expression was only found to respond to acutely administered 1,25(OH) 2 D 3 , the mRNA levels being unaltered following continuous exposure to physiological or pharmacological doses of the hormone for 7 days. Time-course studies revealed, however, that induction of the gene was clearly apparent early in the 1,25(OH) 2 D 3 supplementation course but gradually faded by 3 days to return to basal uninduced levels by 7 days, suggesting the presence of intestinal adaptation mechanism(s) which down-regulated the responsiveness in the continuous presence of 1,25 (OH) 2 D 3 . Our data show the lack of effect of calcium alone or in combination with 1,25(OH) 2 D 3 on the in vivo induction of the 24-hydroxylase gene expression in rat intestine. By rapidly reacting to surges in 1,25(OH) 2 D 3 concentrations, the 24-hydroxylase efficiently controls the amount of 1,25(OH) 2 D 3 in intestine as the first step in the biotransformation pathway aimed at the irreversible clearance of the secosteroid hormone. (J Bone Miner Res 1995 ;10 :1148-1157)

Hepatic drug metabolism was investigated in female Sprague—Dawley rats fed ad libitum (A) or a restricted diet (R) (implemented from age 1 month), at 1.5, 4.5 and 12 months to determine the short- and long-term effects of caloric restriction. Microsomal cytochrome P-450 content and NADPH cytochrome c reductase activity were not modified by age. While dietary restriction did not affect cytochrome P-450, it significantly increased NADPH cytochrome c reductase activity at all time periods when compared to corresponding A-fed groups. Aniline hydroxylase and aminopyrine N-demethylase activity tended to decrease with age in the A-fed groups but the differences did not prove to be statistically significant. A significant decrease of aminopyrine N-demethylase was observed with age in R rats. A significant reduction of aniline hydroxylase activity was noted in the R groups compared to age-matched A-fed controls. In contrast, aminopyrine N-demethylase activity increased significantly, but only at 1.5 months of age. Glutathione S-transferase activity was augmented between 1.5 and 4.5 months of age, and this was followed by a significant decrease at age 12 months in both A and R groups. Dietary restriction had no effect on this enzymatic activity. The microsomal cholesterol and phospholipid content as well as the cholesterol/phospholipid molar ratio changed significantly between 1.5 and 4.5 months of age but not between 4.5 and 12 months of age. These parameters were unaltered by dietary restriction. In conclusion, in the female Sprague—Dawley rat there are no statistically significant changes in hepatic microsomal components and drug metabolizing capacity between 1.5 and 12 months of age. Dietary restriction resulted in significant changes in enzymes related to drug metabolism which varied with the enzyme examined. In general, these changes were similar after short- or long-term dietary intervention.

The existence of specific, high-affinity opioid binding sites was demonstrated in 21-week-old human fetuses with the use of tritiated etorphine, a non-selective opioid ligand. Binding capacities measured in the brain, the cerebellum and the spinal cord give values of 2.83, 3.71 and 5.42 pmol/g of tissue. Kd values do not vary from one region to the other and are respectively 0.29, 0.35 and 0.33 nM. These results are compared with the characteristics of opioid binding sites found in adults.

The existence of specific binding sites for the tachykinin Substance P was investigated in various regions of the central nervous system of a 28-week-old human foetus. Tritiated Substance P binds with high affinity to various amounts of binding sites in the limbic area of the brain, in the frontal, parietal and occipital cortices as well as in the cerebellum. The presence of these specific sites in the foetus is discussed in relation with the proposed neurotrophic role of Substance P.